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Principal Investigator: Mike Lin
Organization: UNIVERSITY OF SOUTH ALABAMA
Fiscal Year: 2024
Award: $453,573
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Patients in intensive care units are at high risk for long-term health threats including cognitive impairment. The
correlation was only recently revealed after large-scale follow-up cognitive assessments on intensive patient
survivors after their discharge from the hospital. There are testimonials, reviews and calls-to-action on many
critical care websites and in journal issues over the last decade on this public health crisis. Studies have
implicated delirium as a good predictor for long-term cognitive deficit; however, the causative and molecular
mechanisms leading to abrupt cognitive impairment are unclear.
In the past 4 years, our studies have discovered that patients in the intensive care unit who contracted
bacterial pneumonia have elevated levels of cytotoxic amyloids in the bronchoalveolar lavage fluid, plasma,
and the cerebrospinal fluid. Rodent brain slices incubated in the cerebrospinal fluids collected from bacterial
pneumonia-positive patients show dampened hippocampal long-term potentiation. In comparison, synaptic
strengthening is prominent in slices incubated in bacterial pneumonia-negative patients’ cerebrospinal fluid.
Moreover, immunopurified from the cerebrospinal fluid or plasma using selective antibodies against Aβ and 𝜏
oligomers and injected into rodents, these cytotoxins induce neuronal dendritic spine retraction, reduce spine
density, and impair animal learning.
Our previous in vitro studies have implicated that in response to Pseudomonas aeruginosa infection, lung
endothelium produces and releases cytotoxins including Aβ and 𝜏 species, and the cytotoxicity and bioactivity
of these species are dependent upon the bacterial virulence. These endothelium-derived cytotoxins damage
endothelial barrier integrity, hinder vascular repair following injury and, importantly, they are released into the
systemic circulation in vivo. Thus, in this competitive renewal, the studies are designed to test the hypothesis
that bacterial pneumonia-elicited lung endothelium-derived amyloids include pathological Aβ and 𝜏 species
capable of dissemination and initiating aggregation. This work addresses a novel mechanism underlying the
end organ dysfunction by systemically quantify cytotoxins released from endothelium in vitro, in rodents, and in
patient specimens.
Terms: <Acquired brain injury><Active Follow-up><Address><Alzheimer beta-Protein><Alzheimer's Amyloid beta-Protein><Alzheimer's amyloid><Ammon Horn><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β oligomer><Amyloid β-Peptide><Amyloid β-Protein><Amyloidosis><Animals><Antibodies><Aβ><AβO><Bacteria><Bacterial Infections><Bacterial Pneumonia><Blood Plasma><Blood Vessels><Blood capillaries><Brain><Brain Injuries><Brain Nervous System><Brain Vascular><Brain Ventricle><Bronchoalveolar Lavage Fluid><Cerebral Ventricles><Cerebrospinal Fluid><Characteristics><Chemosensitization><Chemosensitization/Potentiation><Circulation><Clinical><CoV pandemic><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Contracting Opportunities><Contracts><Cornu Ammonis><Critical Care><Critical Illness><Critically Ill><Cytotoxin><Delirium><Dendritic Spines><Disturbance in cognition><Dysfunction><ESKAPE><ESKAPE pathogens><Encephalon><Endothelial Cells><Endothelium><Exposure to><Functional disorder><Generations><Health><Hippocampus><Hospitals><Impaired cognition><Impairment><In Situ><In Vitro><Incubated><Induced Neurons><Infection><Injury><Intensive Care Units><Invaded><Isoforms><Journals><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Learning><Long-Term Potentiation><Longterm Potentiation><Lung><Lung Respiratory System><Lung infections><Lytotoxicity><MT-bound tau><Magazine><Mediating><Mice><Mice Mammals><Micro-tubule><Microtubules><Molecular><Molecular Weight><Multi-center clinical study><Multi-site clinical study><Multicenter clinical study><Multisite clinical study><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurologic><Neurological><Neurons><Nosocomial pneumonia><Organ><P aeruginosa><P aeruginosa associated pneumonia><P aeruginosa caused pneumonia><P aeruginosa induced pneumonia><P aeruginosa pneumonia><P aeruginosa-associated pneumonia><P aeruginosa-caused pneumonia><P aeruginosa-induced pneumonia><P. aeruginosa><P. aeruginosa associated pneumonia><P. aeruginosa caused pneumonia><P. aeruginosa induced pneumonia><P. aeruginosa infection><P. aeruginosa pneumonia><P. aeruginosa-associated pneumonia><P. aeruginosa-caused pneumonia><P. aeruginosa-induced pneumonia><Pathologic><Patients><Peripheral><Phosphorylation><Physiopathology><Plasma><Plasma Serum><Pneumonia><Potentiation><Production><Protein Isoforms><Protein Phosphorylation><Pseudomonas aeruginosa><Pseudomonas aeruginosa associated pneumonia><Pseudomonas aeruginosa caused pneumonia><Pseudomonas aeruginosa induced pneumonia><Pseudomonas aeruginosa infection><Pseudomonas aeruginosa pneumonia><Pseudomonas pyocyanea><Public Health><Pyramidal neuron><Reporting><Research Specimen><Reticuloendothelial System, Serum, Plasma><Rodent><Rodentia><Rodents Mammals><S aureus><S. aureus><Slice><Specimen><Spinal Column><Spine><Staph aureus><Staphylococcus aureus><Survivors><Synapses><Synaptic><T3SS><Tail><Testing><Type III Secretion System><Type III Secretion System Pathway><Vascular Endothelium><Veins><Vertebral column><Viral><Viral Pneumonia><Virulence><Virulent><Work><a beta peptide><abeta><abeta deposition><abeta oligomer><abnormal brain function><abnormally aggregated tau protein><acronyms><active followup><amyloid beta><amyloid beta deposition><amyloid beta oligomer><amyloid disease><amyloid β deposition><amyloid-b protein><aβ deposition><aβ oligomer><backbone><bacteria infection><bacteria pneumonia><bacterial disease><beta amyloid fibril><brain cell><brain damage><brain dysfunction><brain impairment><brain parenchyma><brain-injured><capillary><cerebral spinal fluid><cerebral vascular><cerebro-vascular><cerebrovascular><cognitive assessment><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><cognitive testing><communicable disease transmission><coronavirus pandemic><cytotoxic><cytotoxicity><delirious><dendrite spine><density><design><designing><disease transmission><dysfunctional brain><filamentous tau inclusion><follow up><follow-up><followed up><followup><healthcare-associated pneumonia><high risk><hippocampal><hippocampal pyramidal neuron><hospital acquired pneumonia><hospital associated pneumonia><iNeuron><in vivo><infected with P. aeruginosa><infected with Pseudomonas aeruginosa><infectious disease transmission><injuries><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><neuronal><neurotoxic><neurotropic><novel><oAβ><oligomeric amyloid beta><oligomeric amyloid-β><paired helical filament of tau><pathogen><pathophysiology><prion-like><pulmonary><pulmonary infections><repair><repaired><response><self-aggregate tau><soluble amyloid precursor protein><spinal fluid><synapse><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau expression><tau factor><tau fibrillization><tau filament><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><type 3 secretion system><vascular><vascular bed><web site><website><τ Proteins><τ aggregation><τ expression>